Nearly one-half of patients infected with the human immunodeficiency virus (HIV) have depression. The effect of depression on this population has profound implications for disease progression, in part related to adherence to antiviral medication. However, neither the unique mechanism(s) by which depression may arise , nor exploration of appropriate antidepressant regimens has been adequately addressed. Untreated depression in HIV+ individuals can promote risk-taking behavior leading to further spread of the disease. As with depression due to other causes, an attractive hypothesis involves a deficit in serotonergic (5-HT) transmission. The 5-HT deficiency-related disorders, i.e., aggressive and suicidal behavior, alcoholism, affective disorders, sexual dysfunction and dementia, have been widely reported in HIV+ individuals. One explanation may be that cytokines released in the periphery from macrophages and from activated microglia within the central nervous system (CNS), may provoke hyperactivity of the kynurenine pathway, an alternative route of tryptophan metabolism that effectively depletes CNS 5-HT levels and produces quinolinic acid, an excitotoxin, that may damage 5-HT neurons. We intend to assess the integrity of the 5-HT system in HIV+ individuals who are depressed using positron emission tomography (PET) and [11C] DASB, a new, selective ligand for the 5-HT transporter (5-HTT). We will compare 5-HTT levels in HIV+ individuals who are depressed with those who are not and to healthy controls. Relative to healthy controls, we expect to find a 5-HTT deficit in HIV+ individuals who are not depressed, but not to the extent seen in those who are. We will recruit patients to our study groups carefully, including only individuals who possess the short (s) allele due to the polymorphism at the 5' end of the promoter region of 5-HTT. The small sample size will also enable us to control easily for co-morbid drug abuse and differences in antiretroviral regimens. In addition to investigating 5-HTT as a possible imaging biomarker, the overall goal of this proof-of-principle study is to provide sufficient preliminary data to undertake a more complete assessment of 5-HT transmission in HIV-related depression that will include longitudinal studies of treatment effects in a wider, more heterogeneous population of affected individuals.